The nervous system is roughly divided into central nervous system and peripheral nervous system, and the peripheral nervous system particularly takes charge of neurotransmission by connecting the brain and spine with somatic peripheries. The peripheral nervous system can be classified into somatic nervous system (cerebrospinal nervous system) and autonomic nerve system. Additionally, the somatic nervous system is divided into cranial nerves and spinal nerves. Also, when the somatic nervous system is functionally classified, those which transmit a neural signal (excitation) generated from a sensory receptor to the central nerves are classified into afferent or sensory nerve fiber, while those which transmit a neural signal directing from the brain and spine toward effector organs such as muscles and glands are classified into efferent or motor nerve fiber. Cranial nerves are peripheral nerves extended from the brain and 12 pairs thereof are known. Some of them consist of sensory nerve fibers; some of them consists of motor nerve fibers; and some of them consists of mixed nerve fibers. Each of the first to twelfth nerve pairs is called olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, auditory nerve, glossopharyngeal nerve, vagus nerve, accessory nerve and hypoglossal nerve. Among them, as nerves consisting of the sensory or mixed nerve fibers, olfactory nerve, optic nerve, trigeminal nerve, facial nerve, auditory nerve, glossopharyngeal nerve and vagus nerve are known. The spinal nerves are peripheral nerves extended from the spine and respective 31 pairs are known. Namely, 8 pairs of cervical nerve, 12 pairs of breast nerve, 5 pairs of lumbar nerve, 5 pairs of sacral nerve and a pair of coccyx nerve are known. All of the spinal nerves consist of mixed nerve fibers and contain sensory fibers (dorsal roots) extend to the skin and the like and motor fibers (ventral roots) extend to skeletal muscle.
The sensory nerve fibers, namely sensory nerves, take charge of a function to accurately transfer stimuli such as light, sound, temperature and touch received by sensory receptors such as optic organ, auditory organ, olfactory organ, gustatory organ and the skin to the central nervous system. The neural signals transferred to the central nervous system are finally transferred to each sensory area of the cerebral cortex, for example, visual area, auditory area and the like, and the sensation is normally recognized thereby. However, there is a case in which various neuropathies of these sensory nerves such as cell death and demyelination are induced through damages of axons, myelin sheaths, Schwann cells or the like caused, for example, by viral infection, tumor, cancer, diabetes mellitus, ischemia, injury, compression, drugs, radiotherapy and the like. As a result, since correct neurotransmission is not carried out in a sensory nerve which caused a disorder, for example, diseases such ad hearing loss and neuropathic pain are generated. In addition to these, there is a neuropathy in which not only a specific sensory nerve but also various peripheral nerves including sensory nerves simultaneously undergo damages caused, for example, by metabolic disease, autoimmune disease and the like diseases, injuries, drug intoxication and the like. In this disease, a single nerve, two or more nerves which present in separate regions or a large number of nerves sometimes undergo the disorder simultaneously. Its symptoms are very complex and varied, and include pain, numbness and burning sensation in a peripheral region and proprioceptive sensation reduction, hypopallesthesia, pain (including neuropathic pain), abnormal sensation, cold, heat and the like.
Additionally, the motor unit includes anterior horn cells, efferent axons thereof and all muscle fibers controlled by the axons. It is known that various peripheral nerve system diseases accompanied by motor function disorders including atrophy, weakness or consumption of a muscle (skeletal muscle or the like) are generated when the motor unit undergoes a certain disorder. The peripheral nerve system disease is divided into a neurogenic disease, a myogenic disease and a mixed type disease thereof. Examples of the neurogenic disease include diseases which are generated when any region of from motor nerve cell to neuromuscular junction in motor units undergoes a disorder, and the like. The neurogenic diseases are generated particularly when a cell body, an axon or a neuromuscular junction of the motor unit undergoes a disorder, and their symptoms occur at peripheries of the legs and arms in most cases.
Examples of the peripheral nerve system diseases include lower and upper motor neuron diseases (e.g., amyotrophic lateral sclerosis, paraneoplastic syndrome, progressive bulbar paralysis, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar paralysis, post poliomyelitis syndrome, genetic spinal muscular atrophy (type I spinal muscular atrophy) (Werdnig-Hoffman disease), type II (intermediate) spinal muscular atrophy, type III spinal muscular atrophy (Wohlfart-Kugelberg-Welander disease), (type IV spinal muscular atrophy) and the like); nerve root diseases (e.g., hernia of intervertebral disk, spinal canal stenosis, cervical spondylosis and the like); plexus diseases (e.g., acute brachial plexitis and the like); thoracic outlet compression syndrome; peripheral nerve disorders (e.g., mononeuropathy, multiple mononeuropathy, multiple neuropathy, Guillain-Barre syndrome, genetic neuropathy (e.g., peroneal muscular atrophy (Chalcot-Marie-Tooth disease), hypertrophic interstitial neuropathy (Dejerine-Sottas disease), diabetic peripheral nerve disorders, neurofibromatosis (e.g., peripheral neurofibroma (Recklinghausen disease), central nervefibroma and the like), Proteus syndrome and the like) and the like); or neuromuscular transmission diseases (e.g., myasthenia gravis, amyotonia congenita syndrome, Eaton-Lambert syndrome, botulism, systemic tetany syndrome, Isaacs syndrome and the like) and the like.
However, since the aforementioned peripheral nerve system diseases are diseases whose generation mechanisms are unknown or physical injuries of nerves, so that symptomatic therapy is mainly carried out with the aim of improving the symptoms in their treatment. Clinically useful agents applicable to the fundamental therapy by directly acting upon the nerves which underwent disorders are barely known.
On the one hand, prostaglandins have been known as a metabolite in the arachidonate cascade. It has been known that the action has cyto-protective activity, uterine contractive activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity and the like.
A recent study has proved existence of various PGE subtype receptors possessing a different physiological or pharmacological role from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3, and EP4 (Negishi M., et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
It is described that a prostaglandin-like compound described in EP860430A1 has an EP2 agonistic effect and is useful for a prevention and/or a treatment of immune diseases, asthma, abnormal bone formulation, neuron cell death, liver damage, premature birth, abortion or retinal neuropathy such as glaucoma etc (Patent Reference 1).
It is described that a prostaglandin-like compound described in WO98/34916 has an EP3 agonistic effect and is useful for a prevention and/or a treatment of liver diseases, kidney diseases, pancreatitis or myocardial infarction etc (Patent Reference 2).
It is described that a prostaglandin-like compound described in WO03/074483 has an EP2 agonistic effect and is useful for a prevention and/or a treatment of immune diseases, allergic diseases, neuronal cell death, dysmenorrhea, premature birth, abortion, baldness, retinal neuropathy, erectile dysfunction, arthritis, pulmonary injury, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, hepatic injury, acute hepatitis, liver cirrhosis, shock, nephritis, renal failure, circulatory diseases, systemic inflammatory response syndrome, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, still disease, Kawasaki disease, burn, systemic granuloma, ulcerative colitis, Crohn disease, hypercytokinemia at dialysis, multiple organ failure, or bone diseases etc (Patent Reference 3).
It is described in WO04/089411 that the combination of the compound which has an EP2 agonistic effect and the compound which has EP3 agonistic effect is useful for spinal canal stenosis (Patent Reference 4).
It is described in WO05/053707 that the prostaglandin-like compound is useful as the agent for increasing cauda equina blood flow (Patent Reference 5).
On the one hand, it is known that EP2 receptor, which is the subtype of PGE2 receptor, relates to the protecting effect of nerves in cerebra (Non-Patent Referent 1).
However, it is neither indicated nor described that an EP2 agonist which may have an EP3 agonistic effect has the regenerating or the protecting effect of peripheral nerves.
[Patent Reference 1] EP860430A1
[Patent Reference 2] WO98/34916
[Patent Reference 3] WO03/074483
[Patent Reference 4] WO04/089411
[Patent Reference 5] WO05/053707
[Non-Patent Referent 1] Nurobiology of Disease, 24, 1, 257-268 (2004)